Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy

Background: West syndrome (WS) is characterized by the onset of epileptic spasms usually within the first year of life. Global developmental delay with/without regression is common. Advances in high-throughput sequencing have supported the genetic heterogeneity of this condition. To better understand the genetic causes of this disorder, we investigated the results of targeted exome sequencing in 29 patients with WS. Methods: Whole exome sequencing (WES) was performed on an Ion ProtonTM and variant reporting was restricted to sequences of 620 known epilepsy genes. Diagnostic yield and treatment impact are described for 29 patients with WS. Results: A definitely/likely diagnosis was made in 10 patients (34%), which included 10 different genes (ALG13, PAFAH1B1, SLC35A2, DYNC1H1, ADSL, DEPDC5, ARX, CDKL5, SCN8A, STXBP1) known to be associated with epilepsy or WS. Most variants were de novo dominant (X-linked/autosomal) except for ARX (X-linked recessive) and ADSL (autosomal recessive). 4 out of 10 (40%) had a genetic diagnosis with potential treatment implications. Conclusions: These results emphasize the genetic heterogeneity of WS. The high diagnostic yield, along with the significant genetic variability, and the potential for treatment impact, supports the early use of this testing in patients with unexplained WS.

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Diagnostic yield and clinical effects of exome sequencing analysis in patients with early-onset scoliosis

The Lancet ◽

10.1016/s0140-6736(19)32415-8 ◽

2019 ◽

Vol 394 ◽

pp. S79

Author(s):

Sen Zhao ◽

Yuanqiang Zhang ◽

Weisheng Chen ◽

Shengru Wang ◽

Pengfei Liu ◽

...

Keyword(s):

Exome Sequencing ◽

Early Onset ◽

Diagnostic Yield ◽

Early Onset Scoliosis ◽

Clinical Effects ◽

Sequencing Analysis

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High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing

Clinical Genetics ◽

10.1111/cge.13038 ◽

2017 ◽

Vol 92 (6) ◽

pp. 594-605 ◽

Cited By ~ 11

Author(s):

Yoo-Mi Kim ◽

Yun-Jin Lee ◽

Jae Hong Park ◽

Hyoung-Doo Lee ◽

Chong Kun Cheon ◽

...

Keyword(s):

Exome Sequencing ◽

Diagnostic Yield ◽

Growth Disorders ◽

Targeted Exome Sequencing ◽

High Diagnostic Yield

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Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-onset Epilepsy

10.1101/139329 ◽

2017 ◽

Cited By ~ 1

Author(s):

Michelle Demos ◽

Ilaria Guella ◽

Marna B. McKenzie ◽

Sarah E. Buerki ◽

Daniel M. Evans ◽

...

Keyword(s):

Exome Sequencing ◽

Early Onset ◽

Diagnostic Yield ◽

Genetic Diagnosis ◽

Diagnostic Process ◽

Supporting Evidence ◽

Potential Cost ◽

Epilepsy Diagnosis ◽

Clinical Benefits ◽

The Impact

AbstractBackgroundTo examine the impact on diagnosis, treatment and cost with early use of targeted whole-exome sequencing (WES) in early-onset epilepsy.MethodsWES was performed on 50 patients with early-onset epilepsy (≤ 5 years) of unknown cause. Patients were classified as retrospective (epilepsy diagnosis > 6 months) or prospective (epilepsy diagnosis < 6 months). WES was performed on an Ion ProtonTM and variant reporting was restricted to the sequences of 565 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed.ResultsA likely/definite diagnosis was made in 17/50 patients (34%) with immediate treatment implications in 8/17 (47%). A possible diagnosis was identified in 9 additional patients (18%) for whom supporting evidence is pending. Time from epilepsy onset to genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 143 days prospective versus 2,172 days retrospective). Costs of prior negative tests averaged $8,344 in the retrospective group, suggesting savings of up to $5,110 per patient.InterpretationThese results support the clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.

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Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS)

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106823 ◽

2020 ◽

Vol 58 (1) ◽

pp. 41-47 ◽

Cited By ~ 2

Author(s):

Sen Zhao ◽

Yuanqiang Zhang ◽

Weisheng Chen ◽

Weiyu Li ◽

Shengru Wang ◽

...

Keyword(s):

Exome Sequencing ◽

Molecular Diagnosis ◽

Early Onset ◽

Diagnostic Yield ◽

Early Onset Scoliosis ◽

Chinese Patients ◽

Molecular Diagnostic ◽

Organ Systems ◽

The Us ◽

The Usa

BackgroundEarly-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening.MethodsIn this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited.ResultsAfter ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis.ConclusionES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

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Identification of LAMP2 mutations in early-onset hypertrophic cardiomyopathy by targeted exome sequencing

Journal of Genetic Medicine ◽

10.5734/jgm.2018.15.2.87 ◽

2018 ◽

Vol 15 (2) ◽

pp. 87-91

Author(s):

Inkyu Gill ◽

Ja Hye Kim ◽

Jin-Hwa Moon ◽

Yong Joo Kim ◽

Nam Su Kim

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Exome Sequencing ◽

Early Onset ◽

Targeted Exome Sequencing

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Faculty Opinions recommendation of Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726778190.793548339 ◽

2018 ◽

Author(s):

Stephen Tisch

Keyword(s):

Exome Sequencing ◽

Early Onset ◽

Large Scale ◽

Clinical Exome Sequencing ◽

Generalized Dystonia

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Utility and implications of exome sequencing in early‐onset Parkinson's disease

Movement Disorders ◽

10.1002/mds.27559 ◽

2018 ◽

Vol 34 (1) ◽

pp. 133-137 ◽

Cited By ~ 5

Author(s):

Joanne Trinh ◽

Katja Lohmann ◽

Hauke Baumann ◽

Alexander Balck ◽

Max Borsche ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Exome Sequencing ◽

Early Onset ◽

Early Onset Parkinson’S Disease

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One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01683-x ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Robert Meyer ◽

Matthias Begemann ◽

Christian Thomas Hübner ◽

Daniela Dey ◽

Alma Kuechler ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Uniparental Disomy ◽

Molecular Testing ◽

Main Body ◽

Comprehensive Overview ◽

Maternal Uniparental Disomy ◽

Whole Exome ◽

Silver Russell Syndrome

Abstract Background Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented. Main body We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS. Conclusions WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

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